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RATIONALE: Drugs used in chemotherapy such as gemcitabine work in different ways to stop tumor cells from dividing so they stop growing or die. Pemetrexed disodium may stop the growth of tumor cells by blocking the enzymes necessary for tumor cell growth. Combining gemcitabine with pemetrexed disodium may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of gemcitabine when given together with pemetrexed disodium to see how well it works in treating patients with unresectable or metastatic biliary tract or gallbladder cancer.

Condition or disease

Intervention/treatment

Phase

Extrahepatic Bile Duct CancerGallbladder CancerLiver Cancer

Drug: gemcitabine hydrochlorideDrug: pemetrexed disodium

Phase 1Phase 2

Detailed Description:

OBJECTIVES:

Determine the maximum tolerated dose of gemcitabine when administered with pemetrexed disodium in patients with unresectable or metastatic biliary tract or gallbladder cancer. (Phase I closed to accrual as of Oct. 2005.)

Determine the 6-month survival rate of patients treated with this regimen.

Determine the best objective tumor response rate and duration of best objective tumor response in patients treated with this regimen.

Determine the time to progression and overall survival of patients treated with this regimen.

Determine the toxic effects of this regimen in these patients.

Determine the individual patient variation in toxicity of and/or response to this regimen due to genetic differences in proteins involved in drug response in these patients.

OUTLINE: This is a multicenter phase I dose-escalation study of gemcitabine followed by a phase II study.

Phase I: Patients receive pemetrexed disodium IV over 10 minutes and gemcitabine IV over 30 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity (phase I closed to accrual as of October 2005).

Cohorts of 3-6 patients receive escalating doses of gemcitabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Phase II: Patients receive pemetrexed disodium as in phase I and gemcitabine at the recommended phase II dose.

Patients are followed every 3 months for 1 year and then every 6 months for 4 years.

PROJECTED ACCRUAL: A total of 85 patients will be accrued for this study.

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Ages Eligible for Study:

18 Years and older (Adult, Senior)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

One of the following histologically or cytologically confirmed cancers not amenable to treatment with combined chemotherapy and radiotherapy:

Prior brain metastases treated with surgery or radiosurgery allowed provided treatment was completed at least 4 weeks ago and there is no evidence of CNS progression

No clinically significant pericardial or pleural effusion or ascites unless able to be drained before study entry

Performance status - ECOG 0-2

At least 3 months

Absolute neutrophil count at least 1,500/mm^3

Platelet count at least 100,000/mm^3

Bilirubin no greater than 3 times upper limit of normal (ULN)

AST no greater than 5 times ULN

Creatinine no greater than 1.5 times ULN

Creatinine clearance at least 45 mL/min

Not pregnant or nursing

Negative pregnancy test

Fertile patients must use effective contraception

No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer

Able to tolerate folic acid, corticosteroids, or cyanocobalamin supplements

More than 4 weeks since prior biologic or immunologic therapy

No prior biologic or immunologic therapy for metastatic disease

No concurrent immunotherapy

No concurrent colony-stimulating factors during course 1

No prior chemotherapy for metastatic disease

No prior gemcitabine

Prior chemoembolization allowed provided the following are true:

At least 4 weeks since prior chemoembolization

Evidence of new tumor growth since therapy

At least 6 months since prior chemotherapy used as a radiosensitizer (in adjuvant setting or for locally advanced disease)

No other concurrent chemotherapy

Prior radiofrequency ablation allowed provided the following are true:

At least 4 weeks since prior radiofrequency ablation

Evidence of new tumor growth since therapy

No prior radiotherapy to 25% or more of the bone marrow

More than 4 weeks since prior radiotherapy

No concurrent radiotherapy

Prior embolization allowed provided the following are true:

At least 4 weeks since prior embolization

Evidence of new tumor growth since therapy

No prior pemetrexed disodium

No aspirin or nonsteroidal anti-inflammatory drugs for at least 2 days (5 days for long-acting agents [e.g., piroxicam]) before, during, and for at least 2 days after administration of pemetrexed disodium